Our work on atrophic remodeling of the heart has caused us to appreciate a simple principle in biology: From the cell cycle to the Krebs cycle there is no life without cycles. While the potential for cellular regeneration receives much attention, the dynamics of intracellular protein turnover have received only selective consideration. Although the concept of the "dynamic state of body constituents" exists since the 1940s, the idea that heart muscle cells renew themselves from within is relatively new. For the last 30 years we (and many others) have elucidated the interaction of metabolic pathways for energy provision and contraction of the heart. Work in the field has uncovered novel metabolic regulators of enzyme action, yet the impact of myocardial energy metabolism on myocardial protein turnover has never been considered. We now propose that metabolic signals are putative regulators of myocardial protein synthesis and degradation. In a broad sense, we seek to establish mechanisms underlying the self-renewal of intact cardiomyocytes. The rationale is based on our observation that atrophic remodeling of the heart simultaneously activates pathways of intracellular protein synthesis and degradation.
Specific Aim 1 will determine how metabolic signals regulate protein degradation. It will test the hypothesis that there is a direct link between intermediary metabolism and protein degradation and that the specific molecular mechanisms involve AMPK regulation of ubiquitin ligases.
Specific Aim 2 will identify metabolic signals of protein synthesis. It will test the hypothesis that a direct link also exists between intermediary metabolism and protein synthesis, that carbohydrates regulate mTOR, and that the specific molecular mechanisms involve G6P regulation of TSC2.
Specific Aim 3 will determine how nutrient stress affects metabolic signals and protein turnover.
This aim will test the hypothesis that impaired glucose uptake (IGU) affects protein turnover when nutrients are over abundant, and that IGU protects the heart from allostatic metabolic stress in response to pressure overload. Collectively, the proposed work seeks to identify metabolic signals as regulators of myocardial protein turnover and seeks to broaden the role energy substrate metabolism from a provider of ATP to a regulator of self-renewal of the cardiomyocyte.

Public Health Relevance

The rhythmic pump action of the heart is supported by an integrated system of metabolic energy transfer. Heart cells are, in turn, made up of a large number of different proteins, all of which are continuously degraded and re-made. This self-renewal of the heart muscle cell is a highly regulated, dynamic process. It allows the heart to adapt to a wide range of changes in its environment. We have preliminary evidence to suggest that intermediary metabolites regulate pathways of both protein synthesis and degradation and are, as a consequence, regulators for the self-renewal of the heart. We are now setting out to solidify this evidence. Furthermore, we predict that identifying key metabolic regulators of intracellular protein turnover in the cardiac myocyte will increase our understanding of insulin resistance as a cardioprotective mechanism. Specifically, it is our hypothesis that insulin resistance protects the heart from overstimulation of protein synthesis and enhances cell survival of the stressed heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061483-11
Application #
8309996
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Adhikari, Bishow B
Project Start
1999-01-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
11
Fiscal Year
2012
Total Cost
$375,000
Indirect Cost
$125,000
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Baskin, Kedryn K; Rodriguez, Meredith R; Kansara, Seema et al. (2014) MAFbx/Atrogin-1 is required for atrophic remodeling of the unloaded heart. J Mol Cell Cardiol 72:168-76
Segura, Ana Maria; Dris, Lamia; Massin, Edward K et al. (2014) Heart failure in remission for more than 13 years after removal of a left ventricular assist device. Tex Heart Inst J 41:389-94
Reineke, Erin L; Benham, Ashley; Soibam, Benjamin et al. (2014) Steroid receptor coactivator-2 is a dual regulator of cardiac transcription factor function. J Biol Chem 289:17721-31
Despa, Sanda; Sharma, Savita; Harris, Todd R et al. (2014) Cardioprotection by controlling hyperamylinemia in a "humanized" diabetic rat model. J Am Heart Assoc 3:
Cordero-Reyes, Andrea M; Gupte, Anisha A; Youker, Keith A et al. (2014) Freshly isolated mitochondria from failing human hearts exhibit preserved respiratory function. J Mol Cell Cardiol 68:98-105
Imamura, Minako; Chang, Benny Hung-Junn; Kohjima, Motoyuki et al. (2014) MondoA deficiency enhances sprint performance in mice. Biochem J 464:35-48
Gupte, Anisha A; Hamilton, Dale J; Cordero-Reyes, Andrea M et al. (2014) Mechanical unloading promotes myocardial energy recovery in human heart failure. Circ Cardiovasc Genet 7:266-76
Chintalgattu, Vishnu; Rees, Meredith L; Culver, James C et al. (2013) Coronary microvascular pericytes are the cellular target of sunitinib malate-induced cardiotoxicity. Sci Transl Med 5:187ra69
Harmancey, Romain; Vasquez, Hernan G; Guthrie, Patrick H et al. (2013) Decreased long-chain fatty acid oxidation impairs postischemic recovery of the insulin-resistant rat heart. FASEB J 27:3966-78
Khalaf, Khaled Imad; Taegtmeyer, Heinrich (2013) Clues from bariatric surgery: reversing insulin resistance to heal the heart. Curr Diab Rep 13:245-51

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